Stroke is the third leading cause of mortality and a leading cause of disability in the U.S. Cardioembolic strokes resulting from atrial fibrillation (AF) are particularly devastating, with a 30-day mortality of 25%. The number of individuals with AF is projected to reach 8 million by 2020, and will disproportionately burden the elderly. The challenge and paradox of AF is that many of the risk factors for stroke are also risk factors for hemorrhage, limiting the use of anticoagulant therapy among those at greatest risk. Patients enrolled in clinical trials often bear little resemblance to the higher risk patients in clinical practice making it difficult to extrapolate estimates of treatment efficacy and safety. Trial participants are younger, more often male, less medically complex, less symptomatic, and specifically selected for lower bleeding risk. Despite their greater burden of risk factors, minorities have constituted less than 5% of AF trial populations. Aspirin is a marginally effective therapy in AF and causes bleeding almost as frequently as anticoagulants, particularly in the elderly. For instance, the rate of intracranial hemorrhage has quintupled in recent years, due to expanded use of anticoagulants and antiplatelet therapy in older adults; 46% are fatal. Preventive strategies without attendant bleeding risk are urgently needed to mitigate the impact of stroke in AF. Although proinflammatory stimuli like hyperglycemia, infection, accelerated hypertension, heart failure, and dyslipidemia are potent triggers for thrombin generation, their effect on AF stroke outcomes has not been studied. The anti-inflammatory and antithrombotic properties of HMG CoA-reductase inhibitors (statins) provide a biological rationale to hypothesize reduced severity (size) of AF stroke. Experimental studies report reduced platelet deposition; platelet mediated thrombin generation, and reduced infarct volume. The relations among statins, modifiable and nonmodifiable stroke risk factors, antithrombotic therapy and AF stroke outcomes have yet to be elucidated. To address these knowledge gaps, we will assemble a large cohort of consecutive AF stroke admissions (ischemic stroke and intracranial hemorrhage) from 2006-2010 (n=2,500, 35% underrepresented minority, 43% >75 years of age) from 3 strategic sites to address the following aims: 1. To determine AF stroke disability and 30-day case fatality by age, sex, race/ethnicity; 2. To examine the relation of acute prothrombotic inflammatory triggers on stroke severity in AF; 3. To study the associations of antithrombotic treatment, including statins, and risk factors to stroke severity in AF. Our application will address these aims through the unique and complementary strengths of the collaborating investigators and institutions: Boston Medical Center, University of Alabama, and Geisinger Health System of Pennsylvania. Our application will inform critical knowledge gaps in AF stroke, target strategies to mitigate stroke severity, and assess the relations of antithrombotic and statin therapy to stroke outcomes across the spectrum of stroke risk among diverse AF patient populations. PUBLIC HEALTH RELEVANCE: Reduction of stroke disability and racial/ethnic disparities in stroke deaths is a pressing U.S. health concern. Through this proposal, we aim to identify stroke prevention approaches for key underrepresented demographic subgroups. Our proposal will inform critical knowledge gaps in AF stroke, target strategies to mitigate stroke severity, and assess the effects of antiplatelet, anticoagulant, and statin therapy among diverse AF patient populations across the spectrum of stroke risk.